In the initial stages of diabetes treatment, diet control and exercise therapy contribute to the preferred glycemic control. When these methods lose control of glycemic regulation, insulin or oral hypoglycemic drugs for treatment are urgently needed. There are various hypoglycemic drugs for clinical treatment comprising biguanides, sulfonylurea compounds, insulin resistance improving agents and α-glucosidase inhibitors etc. Due to different adverse effects of the above drugs, said drugs could not meet the needs of long-term therapy. For example, biguanides could increase the risk of lactic acidosis; sulfonylurea compounds could result in symptoms of hypoglycemia; insulin resistance improving agents could be liable to induce edema and heart failure; and α-glucosidase inhibitors could cause abdominal pain, bloating, diarrhea etc. Consequently, development of novel, safer, and much more effective hypoglycemic agents are highly expected to meet the requirement of diabetes treatment.
Research indicates that glucose transportion by cells is conducted by both facilitative (“passive”) glucose transporters (GLUTs) and sodium-coupled (“active”) glucose transporters (SGLTs). Members of SGLTs acting as glucose transporters are mainly distributed in the intestine and the proximal tubules of the kidneys, indicating that SGLTs are responsible for the majority of glucose reuptake in the intestine and the kidneys. SGLTs are considered as potential and ideal antidiabetic targets.
More specifically, SGLT-1 is predominantly expressed in the small intestinal mucosal cells and a few are expressed in the myocardium and kidneys. SGLT-1 modulates intestinal glucose absorption cooperatively with GLUTs. A second Na+-glucose transporter, SGLT-2, is responsible for renal glucose reuptake since its highly expressed in the kidneys. Glucose in the urine is actively attached to epithelial cells of renal tubules from the glomerular filtrate and is reused in cells through SGLT-2 transporters. In such stage, SGLT-2 takes charge of 90% reabsorption while SGLT-1 transports the rest of 10%. The conclusion that SGLT-2 is the major glucose transporter has been further confirmed in animal studies. Renal glycemic reuptake of rats will be significantly suppressed when SGLT-2 mRNA expression of renal cortical cells is inhibited by using specific SGLT-2 antisense oligonucleotides. It indicated that novel SGLT (SGLT-1/SGLT-2) inhibitors, which could realize controlling intestinal glucose absorption as well as inhibiting renal glucose reuptake via regulating glucose transport function, could be ideal potential antidiabetic drugs with improvement of glucose excreted from the urine and systematic effect in reducing blood sugar.
In addition, the application of SGLT inhibitors was also found in the treatment of complications of diabetes, including retinopathy, neuropathy, nephropathy and related diseases such as glucose metabolism (impaired glucose homeostasis), hyperinsulinemia, hyperglycemia and obesity etc. Meanwhile, SGLT inhibitors avoided or alleviated adverse response and improved the patient compliance in combination with existing therapeutic drugs involving sulfonamide, thiazolidinedione, metformin and insulin, etc without influencing the efficacy and lowering the amounts of the drugs.
In conclusion, SGLT inhibitors, especially SGLT-2 inhibitors, proved to be promising candidates for use as antidiabetic drugs and new antidiabetic agents. Although patents CN1989132A, CN1671682A, CN1829729A and WO2010023594A1 have disclosed a series of C-aryl glucoside and derivatives for use as SGLT-2 inhibitors, novel compounds having improved efficacy, pharmacokinetics and safety are still urgently required for diabetes and related metabolic disorders. The present invention discloses compounds of formula (I) and it is found that such compounds have excellent SGLT-2 inhibitory and hypoglycemic effects.